The rapid advances in our understanding of the immune system have let to the synthesis of many exciting theories about thymic and peripheral tolerance. They include thymic deletions, anergy induction, and clonal exhaustion. The latter two can be the results if excessive stimulation, lack of co-stimulation, or activation by closely related peptides. Concurrently, vast amount of knowledge concerning T cell signaling leading to proliferation or apoptosis has been accumulated. Much of this work is being carried out in whole animal models. These progresses in our understanding of T cells tolerance at the thymic and peripheral levels, however, have not addressed the key questions: How do cryptic peptides initiate and maintain an autoimmune response? We anticipate that in a year or so, additional knowledge will bring us closer to providing some clues to this puzzle. New animal models will be established and more insights will be forthcoming. We propose that it will be time to bring together investigators working in areas of T cell activation and tolerance with those in the field to autoimmunity in the hope of providing multidisciplinary interactions that will allow the understanding of the molecular basis of autoimmunity.